American journal of cardiovascular drugs : drugs, devices, and other interventions · 2026
When Methods Matter: An Umbrella Review of Lorundrostat and the Impact of Analytical Decisions on Reported Blood Pressure and Safety Outcomes.
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Elariny Zeyad, Salem Omar, Salaheldin Mohamad Ashraf, Ahmed Adham, Rabie Farida, Sayed Maryam Mohamed, Harish Mohamed, Ali Mohamed, Eliwa Selim Ahmed, Elshorbagy Mohammad, ElHarouni Sara, Abdelmeguid Ahmed, Ahmed Retaj, Nabeh Omnia Azmy
Аннотация
BACKGROUND: Lorundrostat has emerged as a promising therapy for uncontrolled and/or resistant hypertension, with multiple systematic reviews and meta-analyses (SRMAs) evaluating its blood pressure effects and hyperkalemia risk. Despite drawing from identical trials, reported effect sizes varied markedly, warranting an umbrella review.
METHODS: Conducted per the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines and registered in the International Prospective Register of Systematic Reviews (PROSPERO) (CRD420261358169), this umbrella review included SRMAs of lorundrostat in adults with uncontrolled hypertension. Pooled estimates for systolic blood pressure (SBP), diastolic blood pressure (DBP), and hyperkalemia risk were extracted and compared. Methodological quality was assessed using A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR-2), and primary study overlap was quantified via corrected covered area (CCA).
RESULTS: Ten SRMAs were included; seven focused exclusively on lorundrostat, all showing complete overlap (CCA = 100%). Despite this, substantial variability in pooled estimates was observed. Office SBP reductions ranged from - 7.35 to - 13.55 mmHg (the 95% confidence interval [CI] ranged between - 28.57 and 1.47), 24-h ambulatory SBP ranged from - 5.65 to - 7.45 mmHg (the 95% CI ranged between - 13.60 and 2.31), and DBP reductions were relatively consistent at approximately - 3 to - 4 mmHg, but with the 95% CI ranging between - 7.93 and 0.61. Variability stemmed primarily from differences in dose handling, outcome definitions, and analytical approaches. Lorundrostat was consistently associated with elevated hyperkalemia risk (RR 3.19-11.63), though severity was rarely stratified. Methodological quality was predominantly low to critically low.
CONCLUSION: Lorundrostat produces a modest blood pressure reduction in uncontrolled hypertension. Current evidence is constrained by methodological heterogeneity, limited long-term data, and inadequate safety reporting. Standardized analytical approaches and greater transparency are essential. The proposed effect size concordance index (ECI) may complement overlap metrics by capturing agreement in effect magnitude and precision; however, further validation is required.
METHODS: Conducted per the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines and registered in the International Prospective Register of Systematic Reviews (PROSPERO) (CRD420261358169), this umbrella review included SRMAs of lorundrostat in adults with uncontrolled hypertension. Pooled estimates for systolic blood pressure (SBP), diastolic blood pressure (DBP), and hyperkalemia risk were extracted and compared. Methodological quality was assessed using A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR-2), and primary study overlap was quantified via corrected covered area (CCA).
RESULTS: Ten SRMAs were included; seven focused exclusively on lorundrostat, all showing complete overlap (CCA = 100%). Despite this, substantial variability in pooled estimates was observed. Office SBP reductions ranged from - 7.35 to - 13.55 mmHg (the 95% confidence interval [CI] ranged between - 28.57 and 1.47), 24-h ambulatory SBP ranged from - 5.65 to - 7.45 mmHg (the 95% CI ranged between - 13.60 and 2.31), and DBP reductions were relatively consistent at approximately - 3 to - 4 mmHg, but with the 95% CI ranging between - 7.93 and 0.61. Variability stemmed primarily from differences in dose handling, outcome definitions, and analytical approaches. Lorundrostat was consistently associated with elevated hyperkalemia risk (RR 3.19-11.63), though severity was rarely stratified. Methodological quality was predominantly low to critically low.
CONCLUSION: Lorundrostat produces a modest blood pressure reduction in uncontrolled hypertension. Current evidence is constrained by methodological heterogeneity, limited long-term data, and inadequate safety reporting. Standardized analytical approaches and greater transparency are essential. The proposed effect size concordance index (ECI) may complement overlap metrics by capturing agreement in effect magnitude and precision; however, further validation is required.